15-74720646-G-T

Position:

chr15-74720646-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001319217.2(CYP1A1):c.1382C>A(p.Thr461Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,614,122 control chromosomes in the GnomAD database, including 1,560 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.030 ( 108 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1452 hom. )

Consequence

CYP1A1
NM_001319217.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.158

Variant links:

Genes affected

CYP1A1 (HGNC:2595): (cytochrome P450 family 1 subfamily A member 1) This gene, CYP1A1, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. The gene has been associated with lung cancer risk. A related family member, CYP1A2, is located approximately 25 kb away from CYP1A1 on chromosome 15. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

CYP1A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019521713).

BP6

Variant 15-74720646-G-T is Benign according to our data. Variant chr15-74720646-G-T is described in ClinVar as [Benign]. Clinvar id is 3056253.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP1A1	NM_001319217.2 linkuse as main transcript	c.1382C>A	p.Thr461Asn	missense_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5 linkuse as main transcript	c.1382C>A	p.Thr461Asn	missense_variant	7/7
CYP1A1	NM_001319216.2 linkuse as main transcript	c.1295C>A	p.Thr432Asn	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8 linkuse as main transcript	c.1382C>A	p.Thr461Asn	missense_variant	7/7	1	NM_001319217.2	P1	P04798-1

Frequencies

GnomAD3 genomes

AF:

0.0299

AC:

4543

AN:

152156

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00854

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0409

Gnomad ASJ

AF:

0.0922

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0431

Gnomad OTH

AF:

0.0435

GnomAD3 exomes

AF:

0.0309

AC:

7759

AN:

251432

Hom.:

191

AF XY:

0.0316

AC XY:

4300

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00707

Gnomad AMR exome

AF:

0.0253

Gnomad ASJ exome

AF:

0.0864

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0169

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.0427

Gnomad OTH exome

AF:

0.0450

GnomAD4 exome

AF:

0.0402

AC:

58727

AN:

1461848

Hom.:

1452

Cov.:

AF XY:

0.0397

AC XY:

28871

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00869

Gnomad4 AMR exome

AF:

0.0268

Gnomad4 ASJ exome

AF:

0.0880

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0176

Gnomad4 FIN exome

AF:

0.0116

Gnomad4 NFE exome

AF:

0.0445

Gnomad4 OTH exome

AF:

0.0427

GnomAD4 genome

AF:

0.0298

AC:

4541

AN:

152274

Hom.:

108

Cov.:

AF XY:

0.0286

AC XY:

2133

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00852

Gnomad4 AMR

AF:

0.0409

Gnomad4 ASJ

AF:

0.0922

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.0105

Gnomad4 NFE

AF:

0.0431

Gnomad4 OTH

AF:

0.0435

Alfa

AF:

0.0424

Hom.:

426

Bravo

AF:

0.0320

TwinsUK

AF:

0.0453

AC:

168

ALSPAC

AF:

0.0428

AC:

165

ESP6500AA

AF:

0.00933

AC:

ESP6500EA

AF:

0.0485

AC:

417

ExAC

AF:

0.0305

AC:

3708

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.0495

EpiControl

AF:

0.0504

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CYP1A1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.9

DANN

Benign

0.93

DEOGEN2

Benign

0.0094

T;T;T;T;T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.29

T;T;T;.;.;.

MetaRNN

Benign

0.020

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.99

.;.;L;L;L;.

MutationTaster

Benign

0.80

N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.54

.;.;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.50

.;.;T;T;T;T

Sift4G

Benign

0.52

T;T;T;T;T;T

Polyphen

0.013

.;B;B;B;B;B

Vest4

0.072

MPC

0.033

ClinPred

0.0027

GERP RS

2.7

Varity_R

0.10

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over